CN105439939A - Synthetic method of (S)-N-Boc-3-hydroxypiperidine - Google Patents
Synthetic method of (S)-N-Boc-3-hydroxypiperidine Download PDFInfo
- Publication number
- CN105439939A CN105439939A CN201510771570.5A CN201510771570A CN105439939A CN 105439939 A CN105439939 A CN 105439939A CN 201510771570 A CN201510771570 A CN 201510771570A CN 105439939 A CN105439939 A CN 105439939A
- Authority
- CN
- China
- Prior art keywords
- hydroxy piperidine
- boc
- pyroglutamate
- hydroxypiperidine
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a synthetic method of (S)-N-Boc-3-hydroxypiperidine. The synthetic method comprises: hydrogenating 3-hydroxypyridine to obtain 3-hydroxypiperidine; carrying out heating and refluxing on 3-hydroxypiperidine and a resolving agent namely D-pyroglutamic acid in ethanol solution, and cooling to separate out solids so as to obtain (S)-3-hydroxypiperidine D-pyroglutamate; and adding (S)-3-hydroxypiperidine D-pyroglutamate into di-tert-butyl dicarbonate ester under an alkaline condition, and carrying out refining after reaction to obtain (S)-N-Boc-3-hydroxypiperidine. According to the synthetic method disclosed by the invention, by optimizing a synthetic route of (S)-N-Boc-3-hydroxypiperidine and adopting the low-cost and recyclable resolving agent to reduce the production cost, the yield is improved while ensuring the product purity.
Description
Technical field
The present invention relates to medicinal intermediates preparing technical field, be specifically related to the synthetic method of one (S)-N-Boc-3-hydroxy piperidine.
Background technology
Piperidine derivative plays important role in antibacterial, antitumor, field such as treatment virus infection etc. always, and N-Boc-3-hydroxy piperidine is the wherein very important intermediate with chiral structure, has been widely used at pharmaceutical industries tool.
Chemical method mainly comprises following approach:
Route 1 is with the acid of the natural chiral such as L MALIC ACID, L-Glu or L-Asp for raw material, and through the polystep reaction such as condensation, reduction, complex procedures, and chiral starting materials and to go back original reagent expensive, be difficult to industry and amplify.
Route 2 for raw material, after (2S, 3S)-N-(4-chloro-phenyl-)-2,3-dihydroxyl succinamic acid, L-camphorsulfonic acid etc. split, obtains chiral alcohol by recrystallization with the 3-hydroxy piperidine of racemization; Such as, disclose the preparation method of one (S)-N-Boc-3-hydroxy piperidine in Chinese patent literature CN104557674A disclosed in, the method is that 3-hydroxy piperidine is carried out ammonia displacement with L-camphorsulfonic acid ammonium; 3-hydroxy piperidine splits the brilliant salt of preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid in ethanol and methyl tertiary butyl ether system; (S) the brilliant salt of-3-hydroxy piperidine-L-camphorsulfonic acid changes into (S)-N-Boc-3-hydroxy piperidine under the catalysis of ammoniacal liquor; Its synthetic route is as follows:
Route 3 is with the 3-pyridone be easy to get for raw material and cylite are obtained by reacting N-benzyl-3-pyridone quaternary ammonium salt, and sodium borohydride reduction obtains racemization N-benzyl-3-hydroxy piperidine subsequently.Then, under hydrogen shield and the catalysis of palladium carbon, itself and two carbonic acid and the tert-butyl ester react the N-Boc-3-hydroxy piperidine of obtained racemization, and finally carrying out fractionation with D-tartaric acid derivatives obtains (S)-N-Boc-3-hydroxy piperidine; Its reaction scheme is:
Chemical resolution method relative ease, realized the suitability for industrialized production of (S)-N-Boc-3-hydroxy piperidine already, but due to resolution yield low, and resolving agent price is more expensive, causes product cost relatively high.For this reason, process optimization need be carried out to reduce production cost to chemical resolution, and the comprehensive utilization that mother liquor was applied mechanically, split to the efficient recovery of resolving agent is the current both direction can improving improvement.
In order to solve above-mentioned deficiency of the prior art, the present invention proposes a kind of new solution.
Summary of the invention
The object of this invention is to provide the synthetic method of one (S)-N-Boc-3-hydroxy piperidine.
For reaching above-mentioned purpose, providing the synthetic method of one (S)-N-Boc-3-hydroxy piperidine in one embodiment of the present of invention, comprising the following steps:
(1), the hydrogenation of 3-pyridone is obtained 3-hydroxy piperidine;
(2), by 3-hydroxy piperidine and resolving agent D-Pyrrolidonecarboxylic acid reflux in ethanolic soln, cooling separate out solid, obtain (S)-3-hydroxy piperidine D-pyroglutamate;
(3) (S)-3-hydroxy piperidine D-pyroglutamate is added tert-Butyl dicarbonate in the basic conditions, after reaction terminates, obtain (S)-N-Boc-3-hydroxy piperidine through refining.
Concrete synthetic route is:
Abbreviation in the present invention is respectively:
Compound 1:3-pyridone;
Compound 2:3-hydroxy piperidine;
Compound 3:D-Pyrrolidonecarboxylic acid;
Compound 4:(S)-3-hydroxy piperidine D-pyroglutamate;
Compound 5:(S)-N-Boc-3-hydroxy piperidine.
Preferably, the reaction process of step (1) is: 3-pyridone is reacted 32h ~ 60h under the effect of rhodium C catalyst under the condition of hydrogen pressure 4MPa ~ 6MPa, temperature 80 DEG C ~ 100 DEG C, cold filtration after completion of the reaction, filtrate decompression distillation obtains 3-hydroxy piperidine.
Preferably, the detailed process of step (2) is that 3-hydroxy piperidine and D-Pyrrolidonecarboxylic acid are heated to backflow in 95% ethanol, and solid is separated out in cooling, and continue to be cooled to-5 DEG C, suction filtration, frozen water is washed, and obtains 3-hydroxy piperidine D-pyroglutamate.
Preferably, in step (2), the mol ratio of 3-hydroxy piperidine and D-Pyrrolidonecarboxylic acid is 1:0.5 ~ 0.8; Preferred, in step (2), the mol ratio of 3-hydroxy piperidine and D-Pyrrolidonecarboxylic acid is 1:0.55 ~ 0.6.
Preferably, the consumption of rhodium C catalyst is 0.5% ~ 2% of 3-pyridone quality.
Preferably, in step (3), the temperature of reaction of (S)-3-hydroxy piperidine D-pyroglutamate and tert-Butyl dicarbonate is 20 DEG C ~ 30 DEG C, and the reaction times is 3h ~ 6h.
Preferably, the treating process in step (3) comprises extraction, drying, concentrated and recrystallization.
Preferably, the extraction agent of extraction process is ethyl acetate.
In sum, the present invention has the following advantages:
The present invention is by optimizing the synthetic route of (S)-N-Boc-3-hydroxy piperidine, and employing low cost, callable resolving agent reduce production cost, improve yield while ensureing product purity.
Embodiment
Embodiment 1
The synthesis of compound 2 (3-hydroxy piperidine):
In autoclave, add compound 1 (100kg), 5% rhodium carbon (1kg) and water 100L, at hydrogen pressure 5MPa, under 90 DEG C of conditions, react 48h.Be cooled to room temperature, emptying hydrogen, filter, reclaim rhodium C catalyst.Filtrate decompression dewaters, and residuum continues underpressure distillation, collects 67-69 DEG C/26.6Pa, and cooling after fixing obtains white solid 2 (3-hydroxy piperidine) 102kg, yield 96.3%.
The synthesis of compound 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate):
Compound 2 (400kg) and compound 3D-Pyrrolidonecarboxylic acid (225kg) are added in 95% ethanol 500L, reflux, be cooled to-5 DEG C, leave standstill 1h, filter, filter cake frozen water is washed, and dry to obtain white solid ((S)-3-hydroxy piperidine pyroglutamate) 344kg, yield is 55% (calculating for compound 2).Qualified chipal compounds 4 ((S)-3-hydroxy piperidine D-pyroglutamate) can be obtained for 1 time by solvent recrystallization.
The synthesis of compound 5 ((S)-N-Boc-3-hydroxy piperidine):
200kg compound 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate) is dropped in reactor, add 500L water, sodium hydroxide 80kg, add 518kg tert-Butyl dicarbonate (BOC) under room temperature in batches, add rear continuation reaction 4h, add ethyl acetate 300L, aqueous phase is extracted with ethyl acetate (100L × 2). merge organic phase, concentrating under reduced pressure, obtain compound 3 ((S)-N-Boc-3-hydroxy piperidine) 376kg, yield 95%.Aqueous phase with 20% hydrochloric acid acid adjustment, suction filtration reclaim resolving agent.
Embodiment 2
The synthesis of compound 2 (3-hydroxy piperidine):
In autoclave, add compound 1 (110kg), 5% rhodium carbon (1kg) and water 100L, at hydrogen pressure 6MPa, under 85 DEG C of conditions, react 5h.Be cooled to room temperature, emptying hydrogen, filter, reclaim rhodium C catalyst.Filtrate decompression dewaters, and residuum continues underpressure distillation, collects 67-69 DEG C/26.6Pa, and cooling after fixing obtains white solid 2 (3-hydroxy piperidine) 107kg, yield 96.8%.
The synthesis of compound 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate):
Compound 2 (400kg) and compound 3D-Pyrrolidonecarboxylic acid (225kg) are added in 95% ethanol 500L, reflux, be cooled to-5 DEG C, leave standstill 1.5h, filter, filter cake frozen water is washed, and dry to obtain white solid ((S)-3-hydroxy piperidine pyroglutamate) 344kg, yield is 55% (calculating for compound 2).Qualified chipal compounds 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate) can be obtained for 1 time by solvent recrystallization.
The synthesis of compound 5 ((S)-N-Boc-3-hydroxy piperidine):
200kg compound 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate) is dropped in reactor, add 500L water, sodium hydroxide 75kg, add 518kg tert-Butyl dicarbonate (BOC) under room temperature in batches, add rear continuation reaction 3h, add ethyl acetate 300L, aqueous phase is extracted with ethyl acetate (100L × 2). merge organic phase, concentrating under reduced pressure, obtain compound 3 ((S)-N-Boc-3-hydroxy piperidine) 382kg, yield 97%.Aqueous phase with 20% hydrochloric acid acid adjustment, suction filtration reclaim resolving agent.
Embodiment 3
The synthesis of compound 2 (3-hydroxy piperidine):
In autoclave, add compound 1 (100kg), 5% rhodium carbon (1kg) and water 100L, at hydrogen pressure 5MPa, under 90 DEG C of conditions, react 48h.Be cooled to room temperature, emptying hydrogen, filter, reclaim rhodium C catalyst.Filtrate decompression dewaters, and residuum continues underpressure distillation, collects 67-69 DEG C/26.6Pa, and cooling after fixing obtains white solid 2 (3-hydroxy piperidine) 102kg, yield 81.3%.
The synthesis of compound ((S)-N-Boc-3-hydroxy piperidine tartaric acids derivatives salt):
Compound 2 (400kg) and D-tartaric acids derivatives (225kg) are added in 95% ethanol 500L, reflux, be cooled to-5 DEG C, leave standstill 1h, filter, filter cake frozen water is washed, and dry to obtain white solid 4 ((S)-3-hydroxy piperidine tartaric acids derivatives salt) 274kg, yield is 42%.Qualified chipal compounds 4 ((S)-N-Boc-3-hydroxy piperidine tartaric acids derivatives salt) can be obtained for 1 time by solvent recrystallization.
The synthesis of compound 5 ((S)-N-Boc-3-hydroxy piperidine):
200kg compound ((S)-N-Boc-3-hydroxy piperidine tartaric acids derivatives salt) is dropped in reactor, add 500L water, sodium hydroxide 80kg, add 518kg tert-Butyl dicarbonate (BOC) under room temperature in batches, add rear continuation reaction 6h, add ethyl acetate 300L, aqueous phase is extracted with ethyl acetate (100L × 2). merge organic phase, concentrating under reduced pressure, obtain compound 3 ((S)-N-Boc-3-hydroxy piperidine) 259kg, yield 82.5%.Aqueous phase with 20% hydrochloric acid acid adjustment, suction filtration reclaim resolving agent.
Embodiment 4
The synthesis of compound 2 (3-hydroxy piperidine):
In autoclave, add compound 1 (100kg), 5% rhodium carbon (1kg) and water 100L, at hydrogen pressure 5MPa, under 90 DEG C of conditions, react 48h.Be cooled to room temperature, emptying hydrogen, filter, reclaim rhodium C catalyst.Filtrate decompression dewaters, and residuum continues underpressure distillation, collects 67-69 DEG C/26.6Pa, and cooling after fixing obtains white solid 2 (3-hydroxy piperidine) 102kg, yield 96.3%.
The synthesis of compound 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate):
Compound 2 (400kg) and compound L-Pyrrolidonecarboxylic acid (225kg) are added in 95% ethanol 500L, reflux, be cooled to-5 DEG C, leave standstill 1h, filter, filter cake frozen water is washed, and dry to obtain white solid ((S)-3-hydroxy piperidine pyroglutamate) 344kg, yield is 52.2% (calculating for compound 2).Qualified chipal compounds 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate) can be obtained for 1 time by solvent recrystallization.
The synthesis of compound 5 ((S)-N-Boc-3-hydroxy piperidine):
200kg compound 4 ((S)-N-Boc-3-hydroxy piperidine pyroglutamate) is dropped in reactor, add 500L water, sodium hydroxide 80kg, add 518kg tert-Butyl dicarbonate (BOC) under room temperature in batches, add rear continuation reaction 6h, add ethyl acetate 300L, aqueous phase is extracted with ethyl acetate (100L × 2). merge organic phase, concentrating under reduced pressure, obtain compound ((S)-N-Boc-3-hydroxy piperidine) 368kg, yield 94.6%.Aqueous phase with 20% hydrochloric acid acid adjustment, suction filtration reclaim resolving agent.
The present invention is with 3-pyridone for raw material, and by 3-pyridone hydrogenating reduction, D-Pyrrolidonecarboxylic acid chiral separation, the method that piperidine ring nitrogen BOC protects, sodium hydroxide is free prepares crude product, obtains fine work through recrystallization.The present invention establishes the industrial preparative method of (S)-N-Boc-3-hydroxy piperidine of with low cost, the high and low pollution of operational safety, product purity.Yield is improved (42%), purity high (99.6%), and can be applied to suitability for industrialized production.
In addition, what resolving agent of the present invention was selected is D-Pyrrolidonecarboxylic acid, relative to L-Glutimic acid and D-tartaric acids derivatives, in the reactions steps of carrying out compound 5, select D-Pyrrolidonecarboxylic acid be resolving agent embodiment when ensure yield the reaction times relatively low, the reaction times that such as embodiment 1 yield is maximum is 4h, and embodiment 3 and embodiment 4 need the reaction times of 6h to reach maximum yield.
In addition, resolving agent used in step 2 is that D-Pyrrolidonecarboxylic acid is cheap and easy to get, can commercially directly buy.Its cost lower than the D-tartaric acids derivatives of bibliographical information (as (2S, 3S)-N-(4-chloro-phenyl-)-2,3-dihydroxyl succinamic acid), and recoverable, free from environmental pollution, and the rate of recovery and purity also to compare D-tartaric acids derivatives higher.
Claims (9)
1. a synthetic method for (S)-N-Boc-3-hydroxy piperidine, comprises the following steps:
(1), the hydrogenation of 3-pyridone is obtained 3-hydroxy piperidine;
(2), by 3-hydroxy piperidine and resolving agent D-Pyrrolidonecarboxylic acid reflux in ethanolic soln, cooling separate out solid, obtain (S)-3-hydroxy piperidine D-pyroglutamate;
(3) (S)-3-hydroxy piperidine D-pyroglutamate is added tert-Butyl dicarbonate in the basic conditions, after reaction terminates, obtain (S)-N-Boc-3-hydroxy piperidine through refining.
2. the method for claim 1, it is characterized in that: the reaction process of described step (1) is: 3-pyridone is reacted 32h ~ 60h under the effect of rhodium C catalyst under the condition of hydrogen pressure 4MPa ~ 6MPa, temperature 80 DEG C ~ 100 DEG C, cold filtration after completion of the reaction, filtrate decompression distillation obtains 3-hydroxy piperidine.
3. the method for claim 1, is characterized in that: the detailed process of described step (2) is that 3-hydroxy piperidine and D-Pyrrolidonecarboxylic acid are heated to backflow in 95% ethanol, and solid is separated out in cooling, continue to be cooled to-5 DEG C, suction filtration, frozen water is washed, and obtains 3-hydroxy piperidine D-pyroglutamate.
4. method as claimed in claim 1, is characterized in that: in described step (2), the mol ratio of 3-hydroxy piperidine and D-Pyrrolidonecarboxylic acid is 1:0.5 ~ 0.8.
5. method as claimed in claim 1, is characterized in that: in described step (2), the mol ratio of 3-hydroxy piperidine and D-Pyrrolidonecarboxylic acid is 1:0.55 ~ 0.6.
6. method as claimed in claim 1, is characterized in that: the consumption of described rhodium C catalyst is 0.5% ~ 2% of 3-pyridone quality.
7. method as claimed in claim 1, is characterized in that: in described step (3), the temperature of reaction of (S)-3-hydroxy piperidine D-pyroglutamate and tert-Butyl dicarbonate is 20 DEG C ~ 30 DEG C, and the reaction times is 3h ~ 6h.
8. the method for claim 1, is characterized in that: the treating process in described step (3) comprises extraction, drying, concentrated and recrystallization.
9. method as claimed in claim 8, is characterized in that: the extraction agent of described extraction process is ethyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510771570.5A CN105439939B (en) | 2015-11-12 | 2015-11-12 | A kind of synthetic method of (S)-N-Boc-3- hydroxy piperidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510771570.5A CN105439939B (en) | 2015-11-12 | 2015-11-12 | A kind of synthetic method of (S)-N-Boc-3- hydroxy piperidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105439939A true CN105439939A (en) | 2016-03-30 |
| CN105439939B CN105439939B (en) | 2018-12-04 |
Family
ID=55550640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510771570.5A Expired - Fee Related CN105439939B (en) | 2015-11-12 | 2015-11-12 | A kind of synthetic method of (S)-N-Boc-3- hydroxy piperidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105439939B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017572A (en) * | 2017-12-27 | 2018-05-11 | 江苏尚莱特医药化工材料有限公司 | （S）The preparation method of -3- hydroxy piperidines |
| WO2021163676A1 (en) * | 2020-02-16 | 2021-08-19 | Ayala Pharmaceuticals Inc. | Methods of preparing chiral benzodiazepinone derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738793A (en) * | 2003-01-14 | 2006-02-22 | 赛特凯恩蒂克公司 | Compounds, compositions and methods |
| CN101759629A (en) * | 2009-12-22 | 2010-06-30 | 北大方正集团有限公司 | Novel preparation method for sitafloxacin intermediate |
| CN104557674A (en) * | 2015-01-13 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of (S)-N-Boc-3-hydroxypiperidine |
-
2015
- 2015-11-12 CN CN201510771570.5A patent/CN105439939B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738793A (en) * | 2003-01-14 | 2006-02-22 | 赛特凯恩蒂克公司 | Compounds, compositions and methods |
| CN101759629A (en) * | 2009-12-22 | 2010-06-30 | 北大方正集团有限公司 | Novel preparation method for sitafloxacin intermediate |
| CN104557674A (en) * | 2015-01-13 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of (S)-N-Boc-3-hydroxypiperidine |
Non-Patent Citations (1)
| Title |
|---|
| 沈伟艺等: "(S)-1-叔丁氧羰基-3-羟基哌啶的合成", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017572A (en) * | 2017-12-27 | 2018-05-11 | 江苏尚莱特医药化工材料有限公司 | （S）The preparation method of -3- hydroxy piperidines |
| CN108017572B (en) * | 2017-12-27 | 2023-10-17 | 江苏尚莱特医药化工材料有限公司 | Process for the preparation of (S) -3-hydroxypiperidines |
| WO2021163676A1 (en) * | 2020-02-16 | 2021-08-19 | Ayala Pharmaceuticals Inc. | Methods of preparing chiral benzodiazepinone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105439939B (en) | 2018-12-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113999142B (en) | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine | |
| CN105439939A (en) | Synthetic method of (S)-N-Boc-3-hydroxypiperidine | |
| CN109824545B (en) | Preparation method of trans-4-N-Boc-aminocyclohexane carboxylic acid | |
| CN102020584A (en) | Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam | |
| CN109354580B (en) | Preparation method of donepezil hydrochloride | |
| CN108610279B (en) | Novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine | |
| CN108752186B (en) | Preparation method of 2-benzyl-5-trifluoromethylbenzoic acid | |
| CN105399793A (en) | Cholanic acid preparation method | |
| CN109651234B (en) | Synthesis method of donepezil hydrochloride | |
| CN109824520B (en) | Preparation method of cis-4-methylcyclohexylamine | |
| CN110627641A (en) | Preparation method of isoamyl lactate based on supported sodium bisulfate catalyst | |
| CN111100062A (en) | Synthesis method of donepezil hydrochloride | |
| CN108069897B (en) | Method for synthesizing nicotinic acid by using carbon dioxide | |
| CN113666800B (en) | Synthesis method of 4-pentyne-1-alcohol | |
| EP3415500B1 (en) | Method for preparing methylpyrrolidones | |
| CN114105848B (en) | Preparation method of cis-D-hydroxyproline derivative | |
| CN110642725A (en) | DPA synthesis method | |
| CN115181047B (en) | Preparation method of chiral 3- (dimethylamino) pyrrolidine | |
| CN101723879A (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester | |
| CN101696173B (en) | Method for synthesizing o-amino-p- tert butyl phenol | |
| CN112707924A (en) | Synthetic method of 4-aminomethyl phenylboronic acid hydrochloride | |
| CN106397226A (en) | Novel preparation method for tamoxifen | |
| CN116891430A (en) | Synthesis method of dimethylpyridine amine compound | |
| CN105001096A (en) | 4-amino-N-alkyl benzylamine preparation methood |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181204 Termination date: 20191112 |